S237: THE GENETIC SUBTYPES AND THE TUMOR MICROENVIRONMENT SIGNATURES ARE ASSOCIATED WITH DISTINCT OUTCOMES IN PERIPHERAL T-CELL LYMPHOMA
Authors: Yasuhito Suehara, Kana Sakamoto, Manabu Fujisawa, Kota Fukumoto, Yoshiaki Abe, Kenichi Makishima, Sakurako Suma, Takeshi Sugio, Koji Kato, Koichi Akashi, Kosei Matsue, Kentaro Narita, Kengo Takeuchi, Naoya Nakamura, Seishi Ogawa, Shigeru Chiba, Mamiko Sakata-Yanagimoto
Journal: HemaSphere (2023)

Background: Emerging evidence suggests the prognostic impact of the tumor microenvironment (TME) in peripheral T-cell lymphomas (PTCLs). Aims: To better understand PTCL pathobiology, we performed an integrative multi-omics study to explore the genetic subtypes and the TME signatures of PTCLs, especially nodal T-follicular helper T-cell lymphomas (nTFHLs) and PTCL, not otherwise specified (PTCL-NOS). Methods: We performed whole-exome sequencing of 92 nTFHLs and 37 PTCL-NOSs, a total of 129 cases, on the Illumina HiSeq platform. Ninety-two nTFHLs included 85 angioimmunoblastic T-cell lymphomas (AITLs), four nPTCL with TFH phenotypes, two follicular T-cell lymphomas, and one unclassifiable nTFHL. Mapping, mutation calling, and structural variants detection were performed using Genomon-pipeline. Copy number alterations were analyzed using GATK tools. Genetic drivers recurrently observed in more than 5 cases were integrated using non-negative matrix factorization consensus clustering (NMF). We estimated the proportion of immune cell fractions from bulk RNA sequencing data (n=57) using CIBERSORTx and classified the TME signatures using hierarchical clustering. Results: NMF clustering analysis revealed three genetic subtypes within our cohort, except for 10 cases lacking recurrent genetic abnormalities (denoted as cluster 0). Clusters 1 and 3 (C1 and C3) mostly included nTFHL cases (82% and 91%, respectively), while nTFHL pathology contributed to 32% of cluster 2 (C2). C2 was characterized by TP53 mutation, CDKN2A loss, PTEN loss, and chromosomal instability, corresponding to the previously described GATA3-PTCL subtype (Watatani, 2019; Tayla, 2019). IRF4 gain, recognized as a poor prognostic feature of PTCL, was also enriched in C2. The frequencies of genomic alterations involved in TCR-signaling/NF kappa-B, immune surveillance, PI3K/AKT/mTOR, and tumor suppressor were significantly higher in C2 than in the other subtypes. C1 and C3 shared TFH-related genomic alterations, but C3 had significantly higher frequencies of chromosome (Chr) 5 gain, Chr 21 gain, RHOA, IDH2, and CD28 mutations. A higher frequency of rash and higher C-reactive protein levels than the other AITLs characterized C3-AITL. Pairwise association analysis of genomic alterations revealed that multiple TET2 mutations, rather than a single TET2 mutation, significantly co-occurred with IDH2 and RHOA mutations. Compared to C1, significantly inferior survival was observed in C2 (hazard ratio, 2.52; 95% CI, 1.37-4.63; Fig. A) and C3(hazard ratio, 2.14; 95% CI, 1.17-3.89). The TME signatures were divided into CD4 naïve T-cell type, M2-macrophage/CD4 memory T-cell type, and B-cell type. The M2 macrophage signature was significantly associated with shorter overall survival than the B-cell signature (HR: 8.73, 95% CI 2.32-32.8; Fig. B). The C2-genetic subtype was significantly associated with the M2-macrophage signature compared to C1 (64.3% vs. 7.6%, p=0.006, with BH correction; Fig. C). mTORC1 signaling was enriched in the M2-macrophage signature compared to CD4 naïve and B-cell signatures. Furthermore, AKT and PI3K/mTOR inhibitors were active for the GATA3-PTCL-like cell line established from the PTCL mouse model (Fukumoto, 2020). Summary/Conclusion: C1 and C3, the two major nTFHL genetic subtypes, showed differences in clinical features and survival outcomes. Poor prognosis subtypes discovered using different approaches, the C2 genetic subtype and the M2-macrophage TME signature, were significantly associated. AKT and PI3K/mTOR inhibitors were therapeutic candidates for this subtype of PTCL.Keywords: Microenvironment, Genetic, Peripheral T-cell lymphoma, Angioimmunoblastic T-cell lymphoma